title: Helper activity of natural killer cells during the dendritic cell-mediated induction of melanoma-specific cytotoxic T cells.
abstract: Natural killer (NK) cells have been shown to mediate important immunoregulatory "helper" functions in addition to their cytolytic activity. In particular, NK cells are capable of preventing maturation-related dendritic cell (DC) "exhaustion," inducing the development of "type-1 polarized" mature DCs (DC1) with an enhanced ability to produce interleukin (IL)-12p70, a factor essential for type-1 immunity and effective anticancer responses. Here we show that the NK cell-mediated type-1 polarization of DCs can be applied in the context of patients with advanced cancer to enhance the efficacy of DCs in inducing tumor-specific cytotoxic T lymphocytes. NK cells isolated from patients with late-stage (stage III and IV) melanoma responded with high interferon-γ production and the induction of type-1-polarized DCs on exposure to defined combinations of stimulatory agents, including interferon-α and IL-18. The resulting DCs showed strongly-enhanced IL-12p70 production on subsequent T-cell interaction compared with immature DCs (average of 19-fold enhancement) and nonpolarized IL-1β/TNF-α/IL-6/PGE(2)-matured "standard" DCs (average of 215-fold enhancement). Additional inclusion of polyinosinic: polycytidylic acid during NK-DC cocultures optimized the expression of CD80, CD86, CD40, and HLA-DR on the resulting (NK)DC1, increased their CCR7-mediated migratory responsiveness to the lymph node-associated chemokine CCL21, and further enhanced their IL-12-producing capacity. When compared in vitro with immature DCs and nonpolarized standard DCs, (NK)DC1 were superior in inducing functional melanoma-specific cytotoxic T lymphocytes capable of recognizing multiple melanoma-associated antigens and killing melanoma cells. These results indicate that the helper function of NK cells can be used in clinical settings to improve the effectiveness of DC-based cancer vaccines.
authors.affiliation: Department of Surgery, University of Pittsburgh, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213-1863, USA.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Wong
authors.forename: Robbie B
authors.initials: RB
authors.lastname: Mailliard
authors.forename: Stergios J
authors.initials: SJ
authors.lastname: Moschos
authors.forename: Howard
authors.initials: H
authors.lastname: Edington
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: John M
authors.initials: JM
authors.lastname: Kirkwood
authors.forename: Pawel
authors.initials: P
authors.lastname: Kalinski
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D016764:Cell Polarity; D054421:Chemokine CCL21 / Q000276:immunology; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D016898:Interferon-alpha / Q000494:pharmacology*; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D020382:Interleukin-18 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D011070:Poly I-C / Q000494:pharmacology; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D019496:Cancer Vaccines; D054421:Chemokine CCL21; D016898:Interferon-alpha; D020382:Interleukin-18; D018664:Interleukin-12; D007371:Interferon-gamma; D011070:Poly I-C